The CBL-related protein CBLB participates in FLT3 and interleukin-7 receptor signal transduction in pro-B cells

Abstract

The FLT3 receptor tyrosine kinase and its ligand, FL, play an important role in early hematopoietic development. We have found that CBLB, a recently characterized molecule closely related to the CBL protooncogene product, is phosphorylated on tyrosine(s) following FL treatment of JEA2 human pro-B cells and THP1 monocytic cells. Treatment of JEA2 cells with interleukin (IL)-7 induces CBLB phosphorylation as well. FL and IL-7, respectively, induce and increase association of tyrosine-phosphorylated SHC and the p85 subunit of phosphatidylinositol 3'-kinase with CBLB. In these cells, CBLB constitutively binds the GRB2 adaptor predominantly through its N-terminal SH3 domain, to form a complex that is distinct from the GRB2-CBL and GRB2·SOS1 complexes. Together with the fact that CBLB is consistently found in blast cells from acute leukemias and in peripheral blood mononuclear cells, this suggests that CBLB has a role in tyrosine kinase-regulated signaling pathways in many hematolymphoid cells.